Antifungals

Question 1

Amphotericin B

Answer 1

Polyene antibiotic - Binds to ergosterol in fungal cell membranes leading to cell death
gold standard
must be given parenterally as poor oral bioavailability
does not cross BBB
protein bound
biphasic elimination
S/E: Affinity for cholesterol causes renal toxicity via acc in PCT causing renal vasoconstriction and RTA. Monitor UA and renal values. D/C if signs of tubular damage

Question 2

Azoles

Answer 2

Inhibit fungal p450 enzyme necessary for development of ergosterol in fungal cell walls
Triazoles & Imidazoles
- Triazoles include fluconazole and itraconazole. Less effect on mammal steroid synthesis
- Imidazoles include ketoconazole. More endocrine effects
Drugs that are metabolized by p450 (esp H2 receptor antagonists) may delay metabolism of azoles, esp Keto, and lead to higher plasma drug concentrations

Question 3

Ketoconazole & Itraconazole

Answer 3

Lipophilic
Highly protein bound
administer with food
higher absorption in acidic environment so avoid concurrent antacids
Does not go in the CNS or urine
Ketoconazole can be sole agent for systemic mycoses but not as good as AMB.
- GI upset (meals, multiple day dosing)
- Most likely to cause elevated liver enzymes secondary to inducing mammalian p450 enzymes and can lead to fatal hepatotoxicity
Itraconazole more selectively inhibits fungal p450 enzymes than mammalia thus limiting hepatotoxicity.
- Can develop reversible cutaneous lesions